The protective effects of rapamycin on intestinal ischemia/reperfusion induced remote lung injury in mice

抄録

Introduction: The intestinal ischemia/reperfusion (I/R) injury occurs in various clinical settings, such as mesenteric artery occlusion, trauma, and intestinal transplantation. Intestinal I/R injury elicits inflammatory responses within the intestine, including mucosal epithelial cell damage, loss of barrier function, proinflammatory cytokine production, and increased microvascular permeability. These changes develop multiple organ failure, and become fatal. However, the cure is not fully established. The mammalian target of rapamycin (mTOR) plays an important role in cellular proliferation and survival. It has been shown to be focused on a therapeutic target for various diseases such as cancer and inflammation. Herein, this study was designed to determine whether the mTOR inhibitor, rapamycin, had protective effects on intestinal I/R injury in mice.

Methods: The small intestine of C57BL/6 mice was challenged with ischemia by occluding superior mesenteric artery for 1h. Rapamycin was administered intraperitoneally 1h before the induction of ischemia. In mice following intestinal I/R, the survival rate, inflammatory responses and adhesion molecules in the small intestine and lung were assessed. Bacterial cultures were performed using the homogenate samples from lungs. Phagocytic capacity in the alveolar macrophages and the activation of NF-κB in the lung were also assessed.

Results: Treatment with rapamycin significantly improved survival rate after intestinal I/R. Inflammatory markers (TNF-alpha and MPO activity) in the intestinal tissue of rapamycin-treated mice were unchanged but these assays in the lung were attenuated in rapamycin-treated mice along with decreased bacterial culture and increased phagocytic capacity. The activation of NF-κB and downstream expression of adhesion molecules in the lung of rapamycin-treated mice were downregulated.

Conclusion: Treatment with rapamycin improved survival rate via attenuation of intestinal I/R-induced remote lung injury.